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Abstract
Glucocorticoids are among the most potent anti-inflammatory agents that can be used in the treatment of rhinitis. Their mechanisms of action are multiple and complex and a number of reports describe significant systemic effects of locally administered glucocorticoids. In order to evaluate the short-term systemic effects of intranasally administered glucocorticoids, 14 normal healthy subjects were treated with two doses of either budesonide (BUD) or fluticasone propionate (FP) for 2 weeks. Before treatment, at regular intervals during the treatment, 1 week and finally 6 weeks after termination of treatment, the effects on glucocorticoid receptor (GR) and methallothionein (MTIIa) mRNA expression levels were examined in peripheral lymphocytes using a solution hybridization assay. Serum cortisol, osteocalcin and urinary cortisol levels were also determined. An insulin tolerance test (ITT) was performed at the end of the second week of treatment and at the end of the 6-week washout period with no statistically significant change in cortisol response. In peripheral lymphocytes, GR mRNA levels were significantly down-regulated. MTIIa mRNA levels increased significantly. Serum osteocalcin decreased significantly during treatment with both BUD and FP. Serum cortisol decreased after 1 week of treatment whereas urinary cortisol was not affected until the second week of treatment. In conclusion, intranasal glucocorticoids at clinically recommended doses have not only significant systemic effects on adrenal function, but also have an effect on specific gene expression in peripheral lymphocytes. These effects are receptor-dependent, reversible, and according to serum and urinary cortisol levels and ITT, leave the hypothalamic-pituitary-adrenal function intact. Finally, these short-term systemic effects were not associated with any of the noticeable side-effects usually observed during long-term treatment with glucocorticoids.
Journal of Endocrinology (1995) 144, 301–310
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The interplay between the endocrine and immune systems has come into focus in recent years with the insight that endocrine parameters may affect susceptibility to both auto-immune and infectious diseases. Our interest in immunoendocrine regulation led us to investigate the effects of glucocorticoids on Herpes simplex virus type 1 (HSV-1) infections. Glucocorticoids used to treat inflammatory conditions are not yet recommended for HSV-1 therapy, since they have been reported to prolong viral shedding both in vivo and in vitro. Here we report that glucocorticoids did not alter the viral yield in human gingival fibroblast (HGF) cell culture when glucocorticoid treatment and viral infection occured simultaneously, but the viral yield increased when cells were treated with the glucocorticoid dexamethasone (dex) prior to viral infection. We found that viral infection in our primary cell system increased NF-kappaB levels and DNA binding. In addition, the amount of glucocorticoid receptor (GR) increased following viral infection, and HSV-1 infection as such could induce glucocorticoid-driven transcription of a reporter gene in human embryo kidney (HEK) 293 cells stably transfected with GR. Dex treatment did not affect HSV-1-induced binding of p65 to an NF-kappaB element in an electrophoretic mobility shift assay, and acyclovir was still efficient as an anti-viral drug in the presence of dex. Further studies of the observed effects of HSV-1 infection and glucocorticoid treatment on GR and NF-kappaB regulation could give insights into the immunoendocrine mechanisms important for defence and therapy against viral infections.
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in adrenal function (for reviews see Gluckman & Hanson (2004) and Seckl & Holmes (2007) ). Nutritional perturbations, placental dysfunction and fetal glucocorticoid excess are all recognized as key determinants of a poor fetal environment, and
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Glucocorticoid excess causes visceral obesity and its accompanying insulin resistance, dyslipidemia and hypertension. Glucocorticoids enhance preadipocyte (PA) differentiation and increase their aromatase activity (oestrogen production) and there is regional variability in these PA processes. Therefore, we studied human PAs for the presence of, and any regional or gender differences in, glucocorticoid receptors (GRs). Confluent subcultured human subcutaneous (Sc) and visceral (Vis) PAs from both genders contained GRs as assessed by GR gene expression and specific glucocorticoid (dexamethasone) binding. The dissociation constant was similar to that of other human cells and there was no difference between Sc and Vis sites or between males and females. There was significantly less GR mRNA in Vis PAs compared with Sc PAs in females (P=0.008) but not in males. There was less glucocorticoid binding in Vis compared with Sc PAs in females, measured by maximal binding capacity (P=0.035) or single saturating dose glucocorticoid binding (Bssd) (P=0.019). There was no regional difference in specific glucocorticoid binding in males. There was a gender difference with fewer GRs in Vis PAs in females compared with males measured by Bssd (P=0.006). In summary, GRs are present in human PAs. There is a lower GR density in Vis compared with Sc PAs in females, and females have fewer GRs in Vis PAs compared with males. These differences are likely to affect regional aromatase activity and to contribute to the smaller visceral fat mass in females compared with males.
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Muséum National d'Histoire Naturelle, Marine Station of Concarneau, DMPA USM 0401, UMR 7208 CNRS BOREA ‘Biologie des Organismes et Ecosystèmes Aquatiques’, 7 rue Cuvier, CP 32, 75231 Paris Cedex 05, France
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. Glucocorticoid-induced osteoporosis (GIO), in pathological conditions of endogenous hypercortisolism such as Cushing's syndrome ( Mancini et al . 2004 ) or after cortico-therapy, has been well demonstrated in human bone ( Mazziotti et al . 2006 , Canalis et
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Introduction
It is generally considered that adrenocorticotrophin (ACTH) is the only important factor controlling glucocorticoid secretion from the adrenal (suprarenal) cortex. However, there is actually a considerable body of evidence to suggest that adrenal nerves also have a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis.
Morphological evidence
Most undergraduate textbooks state that the adrenal cortex, in contrast to the medulla, has no nerve supply (see references cited by Robinson, Perry, Hardy et al. 1977; Migally, 1979). Recent work, however, has demonstrated that the cortex shares with the medulla both efferent post-ganglionic adrenergic and sensory (afferent) nerve endings, some of which run in the splanchnic nerves while others travel to the gland with blood vessels (Holzwarth, Cunningham & Kleitman, 1987; Kesse, Parker & Coupland, 1988; Mohamed, Parker & Coupland, 1988). This confirms a series of anatomical observations stretching back many years (Alpert, 1931; Willard, 1938) describing an
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effects on offspring. In the non-pregnant animal, immune challenge with either LPS or interleukin-1β (IL-1β) elicits a prominent acute release of glucocorticoids (GCs), accompanied by an increase in circulating levels of the pro-inflammatory cytokines
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Pharmacological doses of glucocorticoids inhibit thyroid function in man and laboratory animals due to suppression of thyrotrophin (TSH) secretion (Wilber & Utiger, 1969). Administration of prednisolone or dexamethasone for 1–2 days results in a suppression of basal serum TSH levels in normal subjects and in patients with primary hypothyroidism, whilst the pituitary TSH reserve capacity, as assessed by the response to synthetic thyrotrophin releasing hormone (TRH), remains unaltered (Wilber & Utiger, 1969; Besser, Ratcliffe, Kilborn, Ormston & Hall, 1971; Haigler, Pittman & Hershman, 1971). However, impairment of serum TSH response to administered TRH does occur in patients treated with glucocorticoids for 1 or more months (Otsuki, Dakoda & Baba, 1973). These studies suggest that glucocorticoids may inhibit TSH secretion at both hypothalamic and pituitary levels but the main effect of the short-term treatment is suppression of TRH production.
Nicoloff, Fisher & Appleman (1970) found that the circadian rhythm of thyroidal
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We have studied the effects of glucocorticoids on the activity and viability of neonatal rat osteoclasts in vitro. In the bone slice assay, glucocorticoids caused a dose-dependent decrease in the amount of bone resorbed, which was accompanied by a parallel decrease in osteoclast number. Loss of osteoclasts was due to their death, which occurred by the process of apoptosis. Evidence for the latter was obtained by a range of techniques, including time-lapse video microscopy, acridine orange staining, DNA fragment detection and transmission electron microscopy. Immunocytochemistry revealed the presence of glucocorticoid receptors in osteoclasts, and glucocorticoid-induced cell death could be prevented by the glucocorticoid receptor antagonist, RU486. These observations suggest that glucocorticoids promote receptor-mediated apoptosis of rat osteoclasts in vitro. This finding may help to explain recent data indicating that, in sharp contrast with their effects on the human skeleton, glucocorticoids inhibit bone resorption and increase bone mass in rats in vivo.
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ABSTRACT
Blood samples were obtained from two male and two female platypuses at various times after capture and anaesthesia for other experimental purposes. In samples obtained during ketamine–xylazine or pregnanediol anaesthesia 15–24 h after capture, the concentration of total glucocorticoids, measured as 'cortisol equivalent' in a radioligand assay, was 207– 620 nmol/l. In samples taken 14–35 h after injection of dexamethasone (0·2 mg/kg) total glucocorticoid concentration was 79–88 nmol/l.
Individual glucocorticoids were isolated on columns of Sephadex LH-20 and measured separately against appropriate standards. In all except two haemolysed samples obtained from a male that died 25 h after capture, the major glucocorticoid behaved as cortisol, contributing 77–94% of the total. The remainder was made up of varying proportions of substances behaving as corticosterone, 11-deoxycortisol and cortisone. In the haemolysed samples from the moribund animal the major reactive substance, contributing 52–54% of the total, behaved as cortisone. The total adrenal gland weight of this animal was 747 mg, compared with 200–286 mg in two others, suggesting preceding exposure to stress.
Equilibrium dialysis and polyacrylamide gel electrophoresis (PAGE) revealed no evidence for a transcortin-like glucocorticoid- and progesterone-binding protein in platypus plasma. However, as in the echidna, there was a heat-labile, high-capacity binding system migrating with albumin on PAGE.
Glucose was undetectable in the plasma of the moribund animal and only 1·7–2·8 mmol/l in the initial plasma samples from the others. In two animals, injection of glucose i.p and dexamethasone i.m. was followed by an increase in the plasma concentration of glucose to the range 3·8–9·9 mmol/l and commencement of normal swimming and feeding activity for the next 36–48 h.
J. Endocr. (1988) 118, 407–415
